Discoidin Domain Receptor 1: A New Class of Receptor Regulating Leukocyte-Collagen Interaction

Yoshimura, Teizo; Matsuyama, Wataru; Kamohara, Hidenobu

doi:10.1385/ir:31:3:219

Cited by 41 publications

(36 citation statements)

References 47 publications

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“…Our results demonstrate that collagen I is able to induce BMP-2 but not BMP-5 expression in human primary lung fibroblasts, suggesting different transcriptional regulatory mechanisms and roles for the different BMPs. A key mechanism, by which DDRs regulate cell adhesion, migration, proliferation, and ECM remodeling, is controlling the expression and activity of MMPs (5,41). Our data show that collagen I induces MMP-2 and MMP-10 but not MMP-9 expression in NHLFs.…”

Section: Discussionmentioning

confidence: 62%

Collagen I Induces Discoidin Domain Receptor (DDR) 1 Expression through DDR2 and a JAK2-ERK1/2-mediated Mechanism in Primary Human Lung Fibroblasts

Ruiz

Járai

2011

Journal of Biological Chemistry

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Discoidin domain receptors (DDRs) DDR1 and DDR2 are receptor tyrosine kinases with the unique ability among receptor tyrosine kinases to respond to collagen. Several signaling molecules have been implicated in DDR signaling, including Shp-2, Src, and MAPK pathways, but a detailed understanding of these pathways and their transcriptional targets is still lacking. Similarly, the regulation of the expression of DDRs is poorly characterized with only a few inflammatory mediators, such as lipopolysaccharide and interleukin-1␤ identified as playing a role in DDR1 expression. DDRs have been reported to induce the expression of various genes including matrix metalloproteinases and bone morphogenetic proteins, but the regulatory mechanisms underlying DDR-induced gene expression remain to be determined. The aim of the present work was to elucidate the molecular mechanisms implicated in the expression of DDRs and to identify DDR-induced signaling pathways and target genes. Our data show that collagen I induces the expression of DDR1 in a dose-and time-dependent manner in primary human lung fibroblasts. Furthermore, activation of DDR2, JAK2, and ERK1/2 MAPK signaling pathways was essential for collagen I-induced DDR1 and matrix metalloproteinase 10 expression. Finally, inhibition of the ERK1/2 pathway abrogated DDR1 expression by blocking the recruitment of the transcription factor polyoma enhancer A-binding protein 3 to the DDR1 promoter. Our data provide new insights into the molecular mechanisms of collagen I-induced DDR1 expression and demonstrate an important role for ERK1/2 activation and the recruitment of polyoma enhancer-A binding protein 3 to the DDR1 promoter. Discoidin domain receptors (DDRs)2 are non-integrin collagen receptors and constitute a unique subfamily of receptor tyrosine kinases containing a discoidin homology region in their extracellular domain (1). There are two related DDRs: DDR1 and DDR2. DDR1 is mainly expressed in epithelial cells, particularly of the lung, kidney, mammary gland, and gastrointestinal tract, whereas DDR2 is primarily found in cells of mesenchymal origin, such as fibroblasts and smooth muscle cells (1, 2). DDR1 is primarily activated by collagens I-IV and VIII, whereas DDR2 responds to collagen I and to a lesser extent to collagens II, III, and V but does not interact with collagen IV (3, 4). DDR2 has one isoform, whereas five DDR1 isoforms are generated by alternative splicing: DDR1a, b, c, d, and e. DDRs have been implicated in the expression of pro-inflammatory mediators and matrix-degrading enzymes and play an important role in processes such as migration, proliferation, extracellular matrix (ECM) remodeling and wound repair (2, 5-7). Moreover, studies in vivo and in vitro have implicated DDRs in various fibrotic and fibroproliferative conditions such as cancer, atherosclerosis, inflammation, arthritis, and fibrosis of the kidney, liver, skin, and lung (1, 2, 8 -13).The wide range of processes regulated upon DDR stimulation suggests that DDRs may exert their effects via mult...

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Section: Discussionmentioning

confidence: 62%

Collagen I Induces Discoidin Domain Receptor (DDR) 1 Expression through DDR2 and a JAK2-ERK1/2-mediated Mechanism in Primary Human Lung Fibroblasts

Ruiz

Járai

2011

Journal of Biological Chemistry

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“…Other novel potential targets of celecoxib identified in our study are genes involved in cellular adhesion and migration, such as DDR1, whose interaction with collagen facilitates adhesion, migration, and intracellular signaling (35), and Ninein, which is a centrosomal protein with a central role in microtubule nucleation and cell division (36,37). Genes for two transcription factors, GATA2 and FOXP1, were among those modulated by celecoxib (38,39), so was the gene for an executioner caspase, CASP7 (40).…”

Section: Celecoxib-modulated Expression In Colon Cancer Cellsmentioning

confidence: 89%

Altered Gene Expression Profiles Define Pathways in Colorectal Cancer Cell Lines Affected by Celecoxib

Yi¹,

Ajaz²,

Stephens³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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It is well established that celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2) and a tested chemopreventive agent, has several COX-2 -independent activities. In an attempt to better understand COX-2 -independent molecular mechanisms underlying the chemopreventive activity of celecoxib, we did global transcription profiling of celecoxib-treated COX-2 -positive and COX-2 -deficient colorectal cancer cell lines. Celecoxib treatment resulted in significantly altered expression levels of over 1,000 to 3,000 transcripts in these cell lines, respectively. A pathway/functional analysis of celecoxib-affected transcripts, using Gene Ontology and Biocarta Pathways and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including metabolism, cell proliferation, apoptotic signaling, cell cycle check points, lymphocyte activation, and signaling pathways. Among these processes, cell proliferation and apoptotic signaling consistently ranked as the highest-scoring Gene Ontology terms and Biocarta Pathways in both COX-2 expresser and nonexpresser cell lines. Altered expression of many of the genes by celecoxib was confirmed by quantitative PCR and at the protein level by Western blotting. Many novel genes emerged from our analysis of global transcription patterns that were not previously reported to be affected by celecoxib. In the future, in-depth work on selected genes will determine if these genes may serve as potential molecular targets for more effective chemopreventive

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“…DDR1 is activated independently of b1 integrin (Vogel et al, 2000). DDR1-collagen interaction facilitates the adhesion, migration, differentiation/maturation and cytokine/ chemokine production of leukocytes (Yoshimura et al, 2005). DDR1 is overexpressed in several tumors including high-grade brain, esophageal and breast cancers (Weiner and Zagzag, 2000).…”

Section: Discussionmentioning

confidence: 99%

Identification of expressed genes characterizing long-term survival in malignant glioma patients

Arao²,

et al. 2006

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Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes coupled with a class prediction model could be used to define subgroups of high-grade gliomas in a more objective manner than standard pathology. RNAs from 29 malignant gliomas were analysed using Agilent microarrays. We identified 21 genes whose expression was most strongly and consistently related to patient survival based on univariate proportional hazards models. In six out of 10 genes, changes in gene expression were validated by quantitative real-time PCR. After adjusting for clinical covariates based on a multivariate analysis, we finally obtained a statistical significance level for DDR1 (discoidin domain receptor family, member 1), DYRK3 (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 3) and KSP37 (Ksp37 protein). In independent samples, it was confirmed that DDR1 protein expression was also correlated to the prognosis of glioma patients detected by immunohistochemical staining. Furthermore, we analysed the efficacy of the short interfering RNA (siRNA)-mediated inhibition of DDR1 mRNA synthesis in glioma cell lines. Cell proliferation and invasion were significantly suppressed by siRNA against DDR1. Thus, DDR1 can be a novel molecular target of therapy as well as an important predictive marker for survival in patients with glioma. Our method was effective at classifying highgrade gliomas objectively, and provided a more accurate predictor of prognosis than histological grading.

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Discoidin Domain Receptor 1: A New Class of Receptor Regulating Leukocyte-Collagen Interaction

Cited by 41 publications

References 47 publications

Collagen I Induces Discoidin Domain Receptor (DDR) 1 Expression through DDR2 and a JAK2-ERK1/2-mediated Mechanism in Primary Human Lung Fibroblasts

Collagen I Induces Discoidin Domain Receptor (DDR) 1 Expression through DDR2 and a JAK2-ERK1/2-mediated Mechanism in Primary Human Lung Fibroblasts

Altered Gene Expression Profiles Define Pathways in Colorectal Cancer Cell Lines Affected by Celecoxib

Identification of expressed genes characterizing long-term survival in malignant glioma patients

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